Process for preparing cyclic N-substituted alpha-imino carboxylic acids

Abstract

The present invention relates to the novel methods of making matrix metalloproteinase inhibitors of Formula (I):

1. A process for preparing a compound of Formula (I): 
       
         
           
           
               
               
           
         
       
       and/or all stereoisomeric forms of the compound of the Formula (I) and/or mixtures of these forms in any ratio, and/or a physiologically tolerated salt of the compound of the Formula (I), wherein:
 R1 is —(C 1 –C 10 )-alkyl where alkyl is linear or branched; or —(C 2 –C 10 )-alkenyl where alkenyl is linear or branched; or —(C 2 –C 10 )-alkynyl where alkynyl is linear or branched; or —(C 1 –C 4 )-alkylphenyl; or —(C 1 –C 4 )-alkyl-(C 3 –C 7 )-cycloalkyl; or —(C 3 –C 7 )-cycloalkyl; or —CH 2 CF 3 ; and 
 
       Q is a radical selected from 
       
         
           
           
               
               
           
         
       
       wherein R 2  is —(C 1 –C 4 )-alkyl, and a is 0, 1, 2, or 3;
 wherein said process comprises 
 a) reacting a heterocyclic carboxylic acid of Formula (V) 
 
       
         
           
           
               
               
           
         
       
       where Q is as defined in Formula (I), with a silylating reagent; and
 b) reacting the product of step a) with chlorosulfonylbiphenylcarbamate of Formula (IV) 
 
       
         
           
           
               
               
           
         
       
       where R1 is as defined in Formula (I). 
     
     
       2. The process of  claim 1  wherein the chlorosulfonylbiphenylcarbamate of Formula (IV) is prepared by chlorinating a compound of Formula (III) 
       
         
           
           
               
               
           
         
       
       wherein R1 is as defined in Formula (I) and X is an alkali metal or hydrogen, with a chlorinating reagent. 
     
     
       3. The process of  claim 2  wherein the compound of Formula (III) is prepared by sulfonating a compound of Formula (II) 
       
         
           
           
               
               
           
         
       
       where R1 is as defined in Formula (III) with a sulfonating reagent and then reacting that product with an alkali metal salt solution. 
     
     
       4. The process of  claim 3  wherein the sulfonating reagent is chlorosulfonic acid, sulfuric acid, sulfuryl chloride, fuming sulfuric acid or sulfur trioxide. 
     
     
       5. The process of  claim 3  wherein the sulfonation is performed in an aprotic solvent. 
     
     
       6. The process of  claim 5  wherein the aprotic solvent in sulfonation is selected from the group of consisting of chloroform, dichloromethane, pentane, heptane, hexane, tetrachloromethane, benzene, toluene, xylene, chlorobenzene, 1,2-dichloroethane, and trichloroethylene. 
     
     
       7. The process of  claim 3  wherein the alkali metal salt solution is a solution of water-soluble alkali metal salts selected from the group consisting of Na 2 SO 4 , K 2 SO 4 , Li 2 SO 4 , Rb 2 SO 4 , Cs 2 SO 4 . 
     
     
       8. The process of  claim 3  wherein the alkali metal salt solution is a solution of water-soluble alkali metal salts selected from the group consisting of NaCl, KCl, LiCl, RbCl, and CsCl. 
     
     
       9. The process of  claim 3 , wherein the sulfonating reagent is present in a ratio of about 1 mol to about 10 mol to 1 mol of a compound of Formula (II). 
     
     
       10. The process of  claim 9 , wherein the sulfonating reagent is present in a ratio of about 1 mol to about 3 mol to 1 mol of a compound of Formula (II). 
     
     
       11. The process of  claim 2  wherein the chlorination is performed in an aprotic solvent. 
     
     
       12. The process of  claim 11  wherein the aprotic solvent in chlorination is chloroform, dichloromethane, pentane, heptane, hexane, tetrachloromethane, toluene, benzene, xylene, chlorobenzene, 1,2-dichloroethane or trichloroethylene. 
     
     
       13. The process of  claim 2  wherein the chlorinating reagent is PCl 5 , POCl 3 , SOCl 2 , triphenylphosphine in CCl 4 , or mixtures thereof. 
     
     
       14. The process of  claim 2 , wherein the chlorinating reagent is present in a ratio of about 1 mol to about 5 mol to 1 mol of a compound of Formula (III). 
     
     
       15. The process of  claim 14 , wherein the chlorinating reagent is present in a ratio of about 1 mol to about 2 mol to 1 mol of a compound of Formula (III). 
     
     
       16. The process of  claim 1  wherein the silylating reaction is performed in a solvent slected from acetonitrile, dichloromethane, chloroform, tetrahydrofuran, toluene, dimethoxyethane, dioxane or diethylene glycol dimethyl ether, or a mixture thereof. 
     
     
       17. The process of  claim 1  wherein the silylating reagent is N,O-bis(trimethylsilyl)acetamide, trimethylsilyl chloride, or a mixture thereof. 
     
     
       18. The process of  claim 1 , wherein a compound of Formula (V) is present in a concentration of about 0.5 mol to about 2 mol to 1 mol of a compound of Formula (IV). 
     
     
       19. The process of  claim 18 , wherein a compound of Formula (V) is present in a concentration of about 0.9 mol to about 1.1 mol to about 1 mol of a compound of Formula (IV). 
     
     
       20. The process of  claim 1 , wherein the silylating reagent is present in a concentration of about 1 mol to about 5 mol to about 1 mol of a compound of Formula (V). 
     
     
       21. The process of  claim 20 , wherein the silylating reagent is present in a concentration of about 2 mol to about 2.5 mol to about 1 mol of a compound of Formula (V). 
     
     
       22. A compound of Formula (III) 
       
         
           
           
               
               
           
         
       
       wherein:
 R1 is —(C 1 –C 10 )-alkyl where alkyl is linear or branched, or —(C 2 –C 10 )-alkenyl where alkenyl is linear or branched, or —(C 2 –C 10 )-alkynyl where alkynyl is linear or branched, or —(C 1 –C 4 )-alkylphenyl, or —(C 1 –C 4 )-alkyl-(C 3 –C 7 )-cycloalkyl, —(C 3 –C 7 )-cycloalkyl or —CH 2 CF 3 ; and 
 X is Li, Na, K, Rb, and Cs. 
 
     
     
       23. A Compound of the Formula IV 
       
         
           
           
               
               
           
         
       
       wherein:
 R1 is —(C 1 –C 10 )-alkyl where alkyl is linear or branched, or —(C 2 –C 10 )-alkenyl where alkenyl is linear or branched, —(C 2 –C 10 )-alkynyl where alkynyl is linear or branched, —(C 1 –C 4 )-alkylphenyl, —(C 1 –C 4 )-alkyl-(C 3 –C 7 )-cycloalkyl, —(C 3 –C 7 )-cycloalkyl or —CH 2 CF 3 .